CHANGING TRENDS IN LUNG CANCER EPIDEMIOLOGY

 CHANGING TRENDS IN LUNG CANCER EPIDEMIOLOGY

Dr Shilpa Chandran¹, Dr Ravindran Chetambath²

¹Resident Trainee, ²Senior Consultant & Chief of Medical Services

Dept. of Pulmonology, Baby Memorial Hospital, Calicut, Kerala

 

Abstract

Lung cancer is one of the deadliest cancers globally and accounts for most of the cancer-related deaths. Lung cancer is mostly attributed to smoking even though exposure to environmental pollutants and occupational agents also contributes to its causation. For the last 2 decades there is a change in epidemiology and histopathological types of lung cancer. More and more women are affected that too at a younger age when compared to their male counterparts. Another important change noticed is the increase in number of adenocarcinoma surpassing previously predominant squamous cell carcinoma. This article reviews the changes in the epidemiological and histopathological trends in lung cancer.

Key Words

Lung Cancer, trends, cigarette smoking

Introduction

Lung cancer is one of the deadliest cancers globally and accounts for most of the cancer-related deaths. In the last century carcinoma of the lung has progressed from an uncommon and obscure disease to one of the most common cancers in the world. In the late 1840s there were only 22 ever published cases of lung cancer. In 1912 Adler identified only 374 published cases.¹ According to GLOBOCAN data 2.21 million lung cancer cases were diagnosed in the year of 2020 worldwide.

 

Figure-1: Estimated age standardized incidence rates in 2020 (World), both sexes, all ages

(Data source GLOBOCAN 2020)

Comprehensive data on lung cancer in India are lacking. According to GLOBOCAN 2020 data lung cancer was ranked the fourth leading cause of cancer in India in all ages and sexes. Furthermore 66,279 of all cancer related deaths were attributed to lung cancer. In India, lung cancer constitutes 6.9 per cent of all new cancer cases and 9.3 per cent of all cancer related deaths in both sexes.

Notable changes in lung cancer epidemiology have occurred over the past decade owing to the changes in smoking patterns, advances in our understanding of the genetics of lung cancer, role of immune systems in the control of lung cancer and options available for lung cancer treatment. Several studies, including a ten year study conducted at  All India Institute of Medical Sciences (AIIMS) Delhi² have reported that adenocarcinoma (ADC) has surpassed squamous cell carcinoma (SCC) as the most common histological subtype of lung cancer. This shift seems to be attributable partly to the changed smoking pattern and the increasing incidence of lung cancer in females and non-smokers. In contrast, Jindal et al in 1990 after a  10 year follow up study reported that SCC is the most common subtype in India.³

Figure-2: Estimated number of new cases in 2020 (India), both sexes, all ages

(Data source GLOBOCAN 2020)

Change in Incidence Among Males and Females

Incidence trends and geographical patterns are different for men and women and primarily reflect historical, cultural and regional differences in tobacco smoking. Risch et al⁴. has proposed a hypothesis that women smokers are at higher risk of lung cancer than men. It was found that the odds ratio for women was almost three times greater than that for men (27.9 vs. 9.6), when smokers with a 40 pack-year smoking history were compared to non-smokers^5, 6. In addition, Zang and Wynder have shown that the odds ratios for major lung cancer types are consistently higher in women than in men at every level of exposure to cigarette smoke and that these gender differences are likely due to the higher susceptibility to tobacco carcinogens in women⁷.

Over the past decade, due to intensive smoking cessation programs and subsequent reductions in tobacco consumption, incidence rates and deaths attributable to lung cancer declined. However, lung cancer incidence rates have not decreased as much as expected. There are increasing evidence showing variations in rates of decline in lung cancer by sex and race/ethnicity. In a study conducted in California by Manali Patel et al in 2017 it is reported that there is an increase in lung cancer incidence among low socioeconomic class females and for adenocarcinoma⁸.

The reasons behind higher female lung cancer rates in recent years have been attributed to smoking. However, others have refuted smoking as the sole reason for the higher incidence rates among females⁷ and suggest that non-smoking related risk factors may be contributing to the higher rates of lung cancer incidence among females as compared with males.

In a recent study, Jemal and colleagues showed continued sex-based incidence differences and presented compelling evidence that these discrepancies may not be attributed to smoking behaviours in the United States¹⁰. The investigators ascertained incidence trends from 1995 to 2014 using the North American Association of Central Cancer Registries and smoking prevalence trends from 1970 to 2016 by race/ethnicity, age, and sex, using the National Health Interview Study. The authors found an overall decrease in the rate of new lung cancer diagnoses, this trend was driven primarily by a decrease in incidence among non-Hispanic white and Hispanic males. The authors noted increased lung cancer incidence rate ratios (IRR) among females as compared with males from the mid-1990s to 2010-2014 [IRR among persons 40–44 increased from 0.82 (95% CI, 0.79–0.85) to 1.13 (95% CI, 1.08–1.18)]. The authors concluded that the patterns of historically higher incidence rates of lung cancer among men than among women have reversed among non-Hispanic whites and Hispanics born since the mid-1960s, and they are not fully explained by sex differences in smoking behaviours. The rate of new cases (incidence) increased 14% among men from 1975 until peaking in 1984, and has since decreased 46%. The rate of new cases increased 120% among women from 1975 until peaking in 1998, and has since decreased 16%.

Few studies reported that the interaction between tobacco carcinogens and endogenous and exogenous sex steroids may be important. Women taking hormone replacement therapy (HRT) or oral contraceptives experienced to have an increased lung cancer incidence. Epidemiologic data on HRT show a significant association between both a younger median age at lung cancer diagnosis and a shorter median survival time. Another clue is the significantly higher number of lung cancer diagnosed women who are largely premenopausal in comparison to diagnosed men in the same age or women with shorter menstrual cycles.

Studies from East Asia have also shown an increased risk of lung cancer in women with shorter menstrual cycles (threefold higher risk) implying a higher number of hormone influences during the reproductive period¹¹.  Death rates increased for both men and women from 1930 until peaking in 1990 at 91.1 per 100,000 for men and in 2002 at 41.6 per 100,000 for women. Over the last 10 years, rates have decreased by 31% for men and 24% for women.

Age Group

Older age is associated with cancer development due to biologic factors that include DNA damage over time and shortening telomeres. According to the American Cancer Society, most people diagnosed with lung cancer are 65 years or older, with the average age at diagnosis being 70 years.

Laura Guarga et. al. studied trends in lung cancer incidence by age and the data suggest a decrease in the absolute number of new cases in men under the age of 70 years and an increase in women aged 60 years or older¹².  Three quarters of lung cancer deaths in 2019 occurred among those aged 65 years of age and older, and 95% among those aged 55 years of age and older.

In a recent study conducted by Anand Mohan et al, majority of the patients were males (82.9%), in the age bracket of 46–70 years, with mean (SD) age of 58 (11.1) years. The mean age remained relatively unchanged over the study time‑period. The proportion of females showed an increasing trend, from 7.9% in 2008 to 27.2% in 2018.²

Histology and Smoking Pattern

In recent years, there has been a great interest in the histological characterization and genomic classification of lung carcinoma due to the availability of several new targeted therapeutic modalities. The use of generic terms such as non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are being questioned.

The cause–effect relationship between cigarette smoking and lung cancer is undisputed. Lung cancers that develop as a result of cigarette smoking present in a wide variety of histological phenotypes. This likely reflects the complexity of cigarette smoke, which contains large numbers of different carcinogens. The most common histological variants of lung cancer related to smoking are squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma and small cell carcinoma, but less common variants of neuroendocrine neoplasms of varying degrees of malignancy are also associated with cigarette smoking. The relationship between cigarette smoking and adenocarcinoma of the lung was previously thought to be less than that between smoking and squamous cell carcinoma and small cell carcinoma, but data over the past few decades convincingly point to a cause–effect relationship for tobacco and adenocarcinoma^13,14. Another major diagnostic category of lung cancer, large cell carcinoma, might represent poorly differentiated squamous cell cancers or adenocarcinomas, and these cancers are also closely related to tobacco use¹³. Major shifts have been recorded for frequencies of the various histological types of lung cancer in many countries, with significant increases in the relative incidence of adenocarcinoma

Devasa et. al. reported that Squamous cell carcinoma rates among males declined 30% or more in North America and some European countries, while changing less dramatically in other areas; small cell carcinoma rates decreased less rapidly. Squamous and small cell carcinoma rates among females generally rose, with the increases especially pronounced in the Netherlands and Norway. In contrast, adenocarcinoma rates rose among males and females in virtually all areas, with the increases among males exceeding 50% in many areas of Europe; among females, rates also rose rapidly and more than doubled in Norway, Italy and France. Rates of all lung cancer types among women and adenocarcinoma among men continue to rise despite declining cigarette use in many Western countries and shifts to filtered/low-tar cigarettes¹⁵.  In the Western countries and most of the Asian countries, adenocarcinoma has surpassed squamous cell carcinoma.

It is widely accepted that the changes in cigarette design are responsible for the shifts in lung cancer pathology. Most notably, with emerging evidence that cigarettes are the major cause of lung cancer, and recognition of cigarette tar as a reservoir of carcinogens, consumers demand for filtered cigarettes. Cigarette filters are designed to trap tars, and filters typically also have small perforations, which are intended to dilute mainstream smoke. In 1950, less than 1% of all cigarettes sold in the USA had filter tips, but by the late 1990s filter cigarettes constituted more than 97% of the US market.

Another important change in cigarette composition over past decades is in the tobacco blends used in cigarette manufacturing, with a general increase in the amounts of stems and ribs used in the cigarette blends. The stems and ribs of burley tobacco have particularly high levels of nitrates. This later trend is of particular significance, because NNK [4- (methyl-nitrosamino)-1-(3-pyridyl)-1-butanone] appears to be a carcinogen highly specific for pulmonary adenocarcinomas in animal studies¹⁶.

In principle, the use of filter cigarettes reduces the levels of both tar and nitrosamines in the mainstream smoke. Although current smokers generally have decreased exposure to tars and the carcinogens in tars (such as polycyclic aromatic hydrocarbons (PAH)), compared with smokers of the past, craving for nicotine (the major addictive substance of cigarette smoke) appears to cause smokers to cover ventilation holes along the sides of the filters, and also inhale more intensely to satisfy the nicotine crave. For example, studies have shown that smokers of filtered cigarettes take more frequent puffs, and increased volume with each puff, resulting in the peripheral lung being exposed to a proportionally higher level of carcinogens¹⁷. The net result of these changes in cigarette design and pattern of smoke inhalation is a transformation in the anatomic distribution of carcinogen exposure as well as significant alterations in the levels of different carcinogens. These changes are commonly attributed for the shifts in lung cancer histology by increasing incidence of peripheral adenocarcinoma and decreasing incidence of central squamous cell carcinoma.

Although the longitudinal and histology-specific lung cancer data are not as extensive for Asian, African, or South American countries, it appears that similar trends pervade worldwide. Lam et. al. studied the lung cancer patterns in Asian population.

To a large extent, overall increases in lung cancer in these countries parallel the increasing consumption of cigarettes, particularly among men and it appears that the same general histological patterns are seen for these cancers as for the smoking-related cancers in North America and Europe. However, lung cancer in Asian women also appears to be increasing in incidence, and in general, these cancers appear to be predominantly adenocarcinoma. This trend appears to involve rural as well as urban women, and although there is no reliable data for cigarette consumption among women in Asia, there is a general impression that this in relatively independent of cigarette smoking¹⁷.

In the initial years of  a 10 year  study conducted by Anand Mohan et al SCC dominated the morphological type of NSCLC but was overtaken by ADC in 2012, and this trend continued till 2018.¹⁶ It should be noted, however, that the distribution of SCC and SCLC remained largely unchanged, while the frequency of NSCLC- NOS declined. This occurred most likely due to the changing practices of pathological reporting keeping in tune with the advancement in immunohistochemical techniques and based on the revision of guidelines for pathological reporting for lung cancer. Another contributory factor may be an increase in the proportion of females over the 10-year period.

Conclusion

In reviewing the available literature, it is evident that lung cancer incidence is increasing among females, that too at a younger age when compared to their male counter parts. Apart from smoking female hormonal influences are also attributed to this higher incidence. The predominant histopathological type now is adenocarcinoma in all age group and in both sexes.

References

1.     Primary Malignant Growths of the Lungs and Bronchi. JAMA. 1912; 59 (26):2334. doi:10.1001/jama.

2.     Mohan A, Garg A, Gupta A, Sahu S, Choudhari C, Vashistha V, Ansari A, Pandey R, Bhalla AS, Madan K, Hadda V, Iyer H, Jain D, Kumar R, Mittal S, Tiwari P, Pandey RM, Guleria R. Clinical profile of lung cancer in North India: A 10-year analysis of 1862 patients from a tertiary care center. Lung India. 2020; 37(3):190-97. doi: 10.4103/ lungindia. 333_19.

3.     Jindal SK, Behera D. Clinical spectrum of primary lung cancer: Review of Chandigarh experience of 10 years. Lung India 1990; 8:94-98.

4. Risch HA, Howe GR, Jain M, et al. Lung cancer risk for female smokers. Science 1994; 263: 1206– 08.
5. Risch HA, Miller AB. Re: are women more susceptible to lung cancer? J Natl Cancer Inst 2004; 96: 1560-61.
6. Zang EA, Wynder EL. Differences in lung cancer risk between men and women: examination of the evidence. J Natl Cancer Inst 1996; 88:183–92.
7. Patel MI, McKinley M, Cheng I, Haile R, Wakelee H, Gomez SL. Lung cancer incidence trends in California by race/ethnicity, histology, sex, and neighborhood socioeconomic status: An analysis spanning 28 years. Lung Cancer. 2017 Jun; 108:140-49.
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10. Seow A, Poh WT, Teh M, Philip E, Wang Y T, Tan W C, et al. Diet, reproductive factors and lung cancer risk among Chinese women in Singapore: evidence for a protective effect of soy in nonsmokers. Int J Cancer 2002; 97:365–71.
11. Guarga L, Ameijide A , Gragera RM, Carulla M, Delgadillo J, Borràs JM, et al. Trends in lung cancer incidence by age, sex and histology from 2012 to 2025 in Catalonia (Spain). Sci Rep 11, 23274 (2021).
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15. Hoffmann D, Rivenson A, Hecht SS. The biological significance of tobacco-specific N-nitrosamines: smoking and adenocarcinoma of the lung. Crit. Rev. Toxicol. 1996; 26: 199–211.
16. Wynder EL, Muscat JE. The changing epidemiology of smoking and lung cancer histology. Environ Health Perspect. 1995;103 (Suppl. 8):143-48.
17. Lam WK, White NW, Chan-Yeung MM. Lung cancer epidemiology and risk factors in Asia and Africa. Int. J. Tuberc. Lung Dis. 2004; 8: 1045–57.

Thunderstorm asthma

 Thunderstorm asthma

Jis B john¹, Ravindran Chetambath²

¹Internal Medicine Trainee, Dept. of Medicine, NHS Trust, UK

²Professor & Senior Consultant, Baby Memorial Hospital, Calicut, India

Introduction

Thunderstorm asthma is a form of allergic asthma occurring after sudden thunderstorms. This can happen suddenly to people in spring or summer when there is a lot of allergens in the air and the weather is hot, dry, windy, and stormy. This can affect large number of inhabitants in a locality and hence local medical services may find it difficult to meet the exigency. This article reviews the important features and clinical significance of thunderstorm asthma.

Keywords

Asthma, thunderstorm, pauci-micronic, pollen grain.

Introduction

Thunderstorm asthma is due to a potent mix of pollen and weather conditions that can trigger severe asthma symptoms in a large number of people over a short period of time. When certain types of thunderstorms react with high grass pollen conditions in the surrounding rural environment, it can result in a fine mixture of pollen fragments in which thunderstorm wind blow the toxic pollen mixture on to populated areas and a large number of people experience sudden breathing difficulties.

Mechanism

Thunderstorm clouds include upward air currents (updrafts) and downward air currents (downdrafts). This contribute to the development of negatively charged particles at the bottom of clouds. When lightning occurs these negatively charged particles are attracted to positively charged objects on the ground.

Pollen grains from grasses get swept up in the wind and carried for long distances. There was a 4-fold increase in closed pollen grains and a 7-fold increase in ruptured pollen grains during thunderstorms. These findings support the potential role of either grass pollen grains or pauci-micronic starch particles in thunderstorm asthma. These latter particles are released from grass pollen grains when they rupture, and are small enough to be inhaled into the lungs.

Role of airborne fungi in thunderstorm asthma is also evaluated. A detailed environmental study during the June 1994 thunderstorm detected Cladosporium, and Alternaria fungal spores¹. A British study has identified increased odds of asthma admissions with elevated levels of airborne fungi such as Cladosporium and broken Alternaria species.

Epidemiology

Thunderstorm asthma events are uncommon. but generally, occur between October and December. Most of the events recorded in Australia have happened in Victoria, particularly in Melbourne, which is thought to be due to the high concentration of ryegrass in the state. A report from Australia, showed a significant increase in patients attending EDs for bronchospasm related symptoms, in relation to two thunderstorms in two different years in Melbourne (154 and 277 for thunderstorms compared with a daily average of 26.2 patients)². In UK thunderstorms mainly affect the South Eastern and East Midlands regions of England during the summer. A report from Canada identified that acute asthma accounted for 5 and 17% of ED visits on thunderstorm asthma days, compared with just 2% on a non-thunderstorm asthma day. It is also reported from Italy and United states.

Hospitals in Delhi have seen an increase in patients reporting with respiratory illnesses during October to December. This is following the crop season in the neighbouring agricultural states and is accompanies by widespread use of firecrackers in the festive season³. For the last few years this season is declared as a health emergency due to large number of residents attending emergency department. At present this is attributed to pollution; however, similarities can be drawn between this episodes and thunderstorm asthma.

Risk factors

Thunder storm asthma develop in people with asthma whose symptoms get worse in springtime, who are allergic to grass pollen, or who get hay fever in springtime and not known to have asthma.

For those with chronic or seasonal asthma or hay fever, the symptoms of thunderstorm asthma pose a serious and potentially fatal threat. This makes it vital to not only make patients aware of potential dangers but also educate them on methods of prevention during the onset of a season. When a large number of people get affected in a locality health services have been seriously affected. During the June 1994 episode⁴, EDs experienced exhaustion of asthma-related supplies including nebulizer face masks, steroid tablets, B2 agonist inhalers and B2 agonist nebulizer solution. During the same event, half of all the regional health authorities in England observed a 6-fold increase in asthma attendances in EDs and reported difficulty in ED service provision.

Additional risk factors

Thunderstorm asthma affects those who have poorly controlled asthma symptoms as assessed by a standard asthma questionnaire, low FEV1 on spirometry or low PEF, higher levels of antibody to grass pollen/molds. (specific IgE), higher levels of eosinophils in the blood or higher levels of exhaled nitric oxide (FeNO).

Clinical features

Patient with hay fever due to grass pollen, suddenly develop difficulty in breathing. Other symptoms are chest tightness and wheeze. Large number of people in a locality gets the attack. It may coincide with sudden change in environmental conditions. Thousands of people develop, almost simultaneously, breathing difficulties, during stormy wind conditions. Most of them are allergic to grass pollens. Few are asthmatic, but majority have only allergic nasal symptoms. Clinical features are typical of asthma

Diagnosis

First step is to establish an allergy to grass pollen before the season with allergy testing. Either use in vitro test or skin prick test. When symptomatic, establish reversible obstruction by spirometry or use peak flow variability to diagnose asthma.

Management

Use a reliever drug as and when you suspect bronchospasm. Use controller medication during the whole season. Leukotriene receptor antagonists (LTRA) and antihistamines are also useful.

Prevention

Most important action is to remain indoor if you have a local forecast of thunderstorm or high levels of grass pollen in the environment. Regular updation on asthma action plans for seasons of high pollen is needed. Keep updated on daily thunderstorm asthma forecasts in a locality. Those who are at risk should stay indoors with windows and doors closed while the storm front passes (if possible). Always consider using asthma reliever inhalers when appropriate.

Conclusion

Thunderstorm asthma can happen suddenly to people in spring or summer when there is a lot of allergens in the air and the weather is hot, dry, windy, and stormy. This may negatively impact the health care services in the regional hospitals. Predicting thunderstorm and the levels of allergens in the ambient air are important and the inhabitants should follow the instructions to avoid development of asthma.

References

1.     U Allitt. Airborne fungal spores and the thunderstorm of 24 June 1994. Aerobiologia 2000; 16(3): 397-40.

2.     Francis Thien, Paul J Beggs, Danny Csutoros, Jai Darvall, Mark Hew, Janet M Davies, et al. The Melbourne epidemic thunderstorm asthma event 2016: an investigation of environmental triggers, effect on health services, and patient risk factors. The Lancet 2018; 2 (6): E255-E263.

3.     Ravindran Chetambath, Jesin Kumar. Air pollution in Delhi and health emergency. The Indian Practitioner November 2019; 72(11): 8-9.

4.     K M Venables, U Allitt, C G Collier, J Emberlin, J B Greig, P J Hardaker, et al. Thunderstorm-related asthma--the epidemic of 24/25 June 1994. Clin Exp Allergy1997 Jul; 27(7):725-36

Pre-Chronic Obstructive Pulmonary Disease (Pre COPD)

 Pre-Chronic Obstructive Pulmonary Disease (Pre COPD)

Pre-Chronic Obstructive Pulmonary Disease (Pre COPD) is when individuals present with respiratory symptoms without spirometrically confirmed airway obstruction. This stage may eventually progress to airflow limitation consistent with a diagnosis of COPD.  Earlier there was an “at-risk” stage (GOLD stage 0), which was defined by the presence of risk factors (smoking) and symptoms (chronic cough and sputum production) in the absence of spirometric abnormalities that qualify for the diagnostic of COPD (1). Many clinicians did not prefer this category, stating that not all these individuals progresses to COPD (2). The diagnosis of chronic obstructive pulmonary disease (COPD) currently requires the demonstration of poorly reversible airflow limitation, defined as a post-bronchodilator FEV1/FVC <0.7. It is observed that patients with a history of exposure to cigarette smoke or other environmental pollutants may have substantial lung pathology and respiratory impairment even in the absence of airflow limitation, as detected by spirometry. Not all of these patients will develop airflow limitation, but many will have considerable respiratory morbidity and a comparable prognosis to those with classical, spirometrically defined COPD. Identifying individuals who will eventually develop airflow obstruction consistent with a diagnosis of COPD at a stage when FEV1/FVC value is >0.7, may enable therapeutic interventions with the potential to modify the course of disease.

There is Step-1 asthma, which is the intermittent asthma and for many years GINA guidelines proposed treatment with as needed short acting beta agonist (SABA). Later it was found out that SABA will not control underlying inflammation and most of these patients will develop persistent asthma due to airway remodeling. Now the treatment of Step-1 asthma is modified by adding anti-inflammatory agents. A similar situation can be proposed in COPD, where in if we can formulate a strategy to arrest the progression of pathology, development of overt COPD can be prevented. The clinical entity of respiratory bronchiolitis- interstitial lung disease (RB-ILD) which develop in smokers is predominantly a restrictive lung disease where FEV1/FEC will always be normal or above normal. The clinical spectrum of this disease has respiratory bronchiolitis, which is essentially small airway obstruction. Treatment suggested are avoidance of smoking and anti-inflammatory agents, preferably steroid. This is completely reversible. If not intervened at this stage, RB-ILD progresses to COPD with airflow limitation.

Pre-COPD relates to individuals of any age who have respiratory symptoms with or without structural and/or functional abnormalities, in the absence of airflow limitation, and who may develop persistent airflow limitation over time. Individuals with symptoms but without spirometrically defined obstruction compose a heterogeneous group, with some having dyspnoea and others having chronic bronchitis. Some of these individuals may never develop spirometrically defined airflow obstruction, whereas others will experience rapid lung function decline and develop overt disease (3,4) This new understanding of COPD provides novel opportunities for prevention, early diagnosis, and intervention (5).

The term pre-COPD has been recently proposed to identify individuals of any age who have respiratory symptoms with/without structural and/or functional abnormalities, in the absence of airflow limitation (FEV1/FVC > 0.7), and who may (or may not) develop persistent airflow limitation (i.e., COPD) over time (6, 7). Individuals with Pre COPD-are likely to demonstrate:

1.     Respiratory symptoms, including cough with sputum production.

2.      Physiologic abnormalities, including low-normal FEV1, reduced DLCO, and/or accelerated FEV1 decline.

3.      Radiographic abnormalities, including airway abnormalities and emphysema.

This is an important stage, which gives a window of opportunity for the clinician as well as patients, to prevent an otherwise progressive, incurable disease with much morbidity and mortality. Considering the economic burden of treating COPD on the individual, family and society, it is very important that every clinician should focus on identifying pre-COPD and intervene with appropriate steps to prevent progression to full blown COPD. Such individuals should be on regular follow up undergoing spirometric evaluation, DLCO measurements and imaging.

References

1. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS GOLD Scientific Committee. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) workshop summary. Am J Respir Crit Care Med. 2001; 163:1256–1276. [PubMed] [Google Scholar]

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Mechano-transduction in Lung Fibrosis

 Mechano-transduction in Lung Fibrosis

 

Abstract

Mechano-transduction is the phenomenon of conversion of mechanical forces to biochemical signals in fibrosis. Knowledge on how mechano-transduction influences the behavior of cells and tissues will help to identify novel therapeutic targets for mechano-modulatory approaches. Innovative therapies based on these advances will potentially transform fibrotic healing into tissue regeneration.

Keywords: Mechanotransduction, Extracellular matrix, Cytoskeleton

Introduction

The typical response to injury anywhere in the body is scar formation, which provides early restoration of tissue integrity rather than functional regeneration. Scar development serves as a rapid ‘patch’ response, providing a survival advantage as an evolutionarily conserved repair mechanism. All phases of wound healing are influenced by mechanical forces and there is increasing evidence that mechanical influences regulate post-injury inflammation and fibrosis across multiple organ systems. The intensity of scar formation and fibrosis is different in all organs. Lung being an organ with heavy collagen network, fibrosis is a usual phenomenon after tissue injury. Although fibrosis in the setting of cutaneous injury is highly visible, there are a variety of organ systems that demonstrate pathologic fibrotic response to injury, including lung tissue in idiopathic pulmonary fibrosis and the cardiovascular system following ischemic insult.

Acute wound healing typically occurs through a complex cascade of carefully orchestrated biochemical and cellular events in overlapping phases like hemostasis, inflammation,  proliferation  and remodeling with scar formation.

Mechanism

Mechanical stress causes an infiltration of inflammatory cells and decreased apoptosis of local cells involved in the healing response, resulting in proliferative scarring¹. Mechanical force regulates fibrosis in part via an inflammatory focal adhesion kinase - extracellular signal-regulated kinase - monocyte chemotactic protein-1 (FAK-ERK-MCP-1) pathway². Impact of FAK signalling on fibrosis formation has been demonstrated in lung tissue using a bleomycin-induced pulmonary fibrosis model in mice^3,4. Bleomycin, originally developed as an anticancer agent, causes an inflammatory response resembling acute lung injury (ALI) and ultimately leads to the development of fibrosis, which can be markedly decreased by FAK inhibition. Through the process of mechano-transduction, cells are able to convert mechanical stimuli into biochemical or transcriptional changes⁵.  This signal transduction involves proteins and molecules of the extra cellular matrix (ECM), the cytoplasmic membrane, the cytoskeleton and the nuclear membrane, eventually affecting the nuclear chromatin at a genetic and epigenetic level. Specifically, the response to continuous mechanical overload is a maladaptive remodeling of myocytes and the ECM, as well as increased interstitial fibrosis. There will be ECM activation through cellular traction forces and extracellular stretch. This is followed by cell surface, trans-membrane mechanotransduction. Next stage is mechanotransduction through cytoskeleton and nuclear mechanotransduction.

Mechano-transduction pathways are also important in the myocardium, as pathological hypertrophy can result from the abnormal cardiac workloads associated with systemic hypertension, aortic stenosis, or myocardial infarction⁶.

Extra Cellular Matrix

Extra Cellular Matrix (ECM) is a dynamic and living component possessing multiple functions, including playing a pivotal role in cell adhesion, migration, differentiation, proliferation, apoptosis and mechanotransduction. Reciprocal communication of mechanical cues between the ECM and cells can even directly influence gene expression, providing at least one mechanism of how physical cues from the ECM are able to alter cell functionality and phenotype. Mechanical forces can expose hidden domains and alter spatial density of growth factors within the ECM, thereby influencing cell behavior. Finally, cytokines such as TGF-β can bind to ECM domains and be released based on mechanical cues. Micro-environmental cues can influence fibroblast proliferation and collagen production via mechanoresponsive cell surface receptors. TGF-ß superfamily have a significant influence on fibrosis and inflammation.

Mediators

Multiple interrelated signaling pathways have been shown to participate in the complex mechanism of intracellular mechano-transduction. Mediators responsible for transducing signals from the biomechanical environment include integrin-matrix interactions, growth factor receptors (for TGF-β), G protein-coupled receptors (GPCRs), mechanoresponsive ion channels (e.g., Ca2+), and cytoskeletal strain responses. Through single-cell RNA sequencing, identified up-regulation of mechano-transduction signaling pathways in the healing grafts. Applying a hydrogel containing a focal adhesion kinase (FAK) inhibitor to the grafts to disrupt mechano-transduction, improved healing and reduced contracture and scar formation, with anti-inflammatory effects in the acute setting and pro-regenerative effects at later phase.

Therapeutic targets

The above findings suggest that FAK inhibition could be beneficial for treatment of injuries. The major therapeutic strategies involving the TGF-β pathway thus include using neutralizing antibodies to TGF-βl and 2, or increasing TGF-β3. Neutralizing antibodies bind directly to the ligand and prevent receptor activation, and TGF-β1 and 2 specific antibodies have been successfully used to reduce fibrosis in a number of organs in animal models. The first clinical trial assessing an anti-TGF-β antibody (metelimumab) was used for patients with systemic sclerosis and demonstrated no significant improvement. A similar lack of benefit was seen in a Phase II clinical trial using imatinib mesylate, an inhibitor of TGF-β and platelet-derived growth factor signaling, for the treatment of scleroderma⁷.

Nintedanib, an antifibrotic agent used in idiopathic pulmonary fibrosis (IPF) is a potent small molecule inhibitor of the receptor tyrosine kinases platelet-derived growth factor (PDGF), fibroblast growth factor (FGF) and vascular endothelial growth factor receptor. Nintedanib interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation, and the secretion of ECM⁸.

Pirfenidone, another antifibrotic agent used in IPF, attenuates the production of transforming growth factor-β1 (TGF-β1). By suppressing TGF-β1, pirfenidone inhibits TGF-β1-induced differentiation of human lung fibroblasts into myofibroblasts, thereby preventing excess collagen synthesis and extracellular matrix production⁹.

Conclusion

A thorough understanding of the various signaling pathways involved scar formation is essential to formulate strategies to combat fibrosis and scarring. While initial efforts focused primarily on the biochemical mechanisms involved in scar formation, more recent research has revealed a central role for mechanical forces in modulating these pathways. Many molecules are being tried to prevent fibrosis based on mechano-transduction such as anti TGF beta 1 and 2. More research is needed to identify different biochemical pathways leading to fibrosis which may help in targeting these molecules to prevent fibrosis. Pirfenidone and nintedanib, presently used as antifibrotic agents in IPF acts by inhibiting various stages of fibroblast proliferation implicated in mechanotransduction.

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